Evaluation of Hypoxia in Primary Melanoma

Prospective Evaluation of Hypoxia in Primary Melanoma

When controlling for tumor present in the Sentinel lymph node (SLN), intranodal hypoxia, as measured by Carbonic Anhydrase IX (CAIX IHC), is associated with worse PFS. This suggests that melanoma tumors may be utilizing deregulated metabolism as a means of propagating themselves to the next station of metastasis. This study aims to prospectively validate previous findings. Patients who are to undergo WLE and SLNB per standard of care (SOC) will be evaluable. It is hypothesized that SLN(s) with increased hypoxia, as measured by pimonidazole staining, will be associated with worse Progression-free Survival (PFS).

Study Overview

• Status: Recruiting
• Conditions: Melanoma
• Intervention / Treatment: Drug: Pimonidazole

Detailed Description

This study aims to prospectively validate previous findings. Having found that deregulated tumor cell metabolism and resultant intra-tumoral hypoxia (ITH) are linked to clinical outcomes in patients with advanced stage melanoma, it was next sought to understand whether hypoxia, utilized as a surrogate of dysregulated metabolism, has significance in patients with earlier stage melanoma. This was done by utilizing banked samples from melanoma patients. Patients with early-stage melanoma who had undergone wide local excision (WLE) and sentinel lymph node biopsy (SLNB) were eligible, involving fifty patients who had a positive SLN, and 50 patients who had a negative SLN. Utilizing novel Vectra panels developed by the Najjar lab, intra-nodal hypoxia was evaluated, as measured by carbonic anhydrase IX (CAIX), it was fund that when controlling for tumor present in the SLN, intranodal hypoxia as measured by CAIX IHC is associated with worse PFS. This suggests that tumors may be utilizing deregulated metabolism as a means of propagating themselves to the next station of metastasis.

• Study Type: Observational
• Enrollment (Estimated): 50

Contacts and Locations

• Study Contact: Name: Amy Rose, RN, BSN; Phone Number: 412-647-8587; Email: kennaj@upmc.edu
• Study Contact Backup: Name: Danielle L Bednarz, RN, BSN; Phone Number: 4126231191; Email: bednarzdl@upmc.edu

Study Locations

• United States
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15232
      • Recruiting
      • UPMC Hillman Cancer Center
      • Contact: Danielle Bednarz, RN, BSN; Phone Number: 412-623-1191; Email: bednarzdl@upmc.edu
      • Contact: Amy Rose, RN, BSN; Phone Number: 412-647-8587; Email: kennaj@upmc.edu
      • Principal Investigator: Yana Najjar, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

Patients with a histological diagnosis of melanoma

Description

Inclusion Criteria:

1. Must be willing and able to provide written informed consent for the study.
2. Must have histologically confirmed melanoma for which a Sentinel Lymph Node Biopsy (SLNB) is indicated per the treating physician.
3. Cutaneous or mucosal melanoma is permitted.

4. Female patients of childbearing potential must have a negative urine or serum pregnancy test within 7 days from the time of pimonidazole administration.

   1. Female subjects of childbearing potential must not be pregnant or breastfeeding. Female subjects will be considered of non-reproductive potential if they:

      1. are postmenopausal (defined as at least 12 months with no menses without an alternative medical cause; in women < 45 years of age a high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a post-menopausal state in women not using hormonal contraception or hormonal replacement therapy. In the absence of 12 months of amenorrhea, a single FSH measurement is insufficient.
      2. have had a hysterectomy and/or bilateral oophorectomy, bilateral salpingectomy or bilateral tubal ligation/occlusion, at least 6 weeks prior to screening.
      3. have a congenital or acquired condition that prevents childbearing.

   2. Female and male subjects of reproductive potential must agree to avoid becoming pregnant or impregnating a partner, respectively, while receiving study drug and 1 week after the dose of study drug for females and 2 weeks for males by complying with one of the following:

      1. practice abstinence from heterosexual activity
      2. use (or have their partner use) acceptable contraception during heterosexual activity.
5. Adequate hematologic function: white blood cells (WBC) ≥ 2,500/μL, platelet count ≥ 100,000/μL, hemoglobin ≥ 8.0 g/dL
6. Adequate renal function: serum creatinine ≤ 2.0 mg/dL
7. Adequate hepatic function: serum alkaline phosphatase, bilirubin, and ALT ≤ twice the institutional upper limit of normal

Exclusion Criteria:

1. Subjects with known chronic immunosuppression (such as biologic agents like infliximab, mycophenolate, methotrexate, prednisone > 20 mg daily).
2. Severe septicemia or severe infection in the 4 weeks prior to study entry.
3. History of previous neuropathy from chemotherapy or other causes not related to cancer.
4. Pregnant subjects or breastfeeding subjects. (Note: A pregnancy test will be administered within 7 days prior to the administration of pimonidazole to female subjects of childbearing potential enrolled in the study.)
5. Subjects with (ECOG) Performance scale of 4 - subjects unable to perform self-care.
6. Subjects who have received an investigational new drug 6 half-lives or two weeks prior to enrollment in this study, whichever is shorter.

Study Plan

How is the study designed?

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort

Intervention / Treatment

Pimonidazole; Single dose of 0.5 gm/m^2 of pimonidazole (approximately 13 mg/kg)

Drug: Pimonidazole; Drug: Pimonidazole Pimonidazole is not used with therapeutic intent, and has a non-hazardous designation. It has been widely used for in vivo evaluation of intratumor hypoxia, and patients will take PO pimonidazole before the scheduled biopsy. Patients receive an oral dose of pimonidazole, a safe chemical tracer up to 24 hours prior to biopsy. Pimonidazole allows for true hypoxia staining; pimonidazole binds hypoxic proteins covalently, creating an antigen that facilitates the imaging, flow cytometry, and scRNA-seq experiments proposed. Pimonidazole has been previously used in patients and is safe and well tolerated, without anticipated adverse events.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Tumor Hypoxia	Hypoxia (decreased oxygen levels) in the primary tumor in patients with primary melanoma as measured by hypoxyprobe staining in primary tumor through CODEX imaging.	Day of surgery
Progression Free Survival	Median number of months from time of surgery to regression, progression or death, whichever occurs first. Progression is defined as observable disease upon visual evaluation of surgical (anatomical) site.	Up to 5 years (from date of surgery)
Sentinel Lymph Node Hypoxia	Hypoxia (decreased oxygen levels) in the sentinel lymph node (SLN) in patients with primary melanoma as measured by hypoxyprobe staining in primary tumor through CODEX imaging.	Day of surgery

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Intra-nodal - intra-tumoral hypoxia correlation	Correlation of hypoxia (decreased oxygen levels) in the sentinel lymph node (SLN) with that of the primary tumor in patients with primary melanoma as measured by hypoxyprobe staining in primary tumor through CODEX imaging.	Day of surgery

Collaborators and Investigators

• Sponsor: Yana Najjar
• Collaborators: Hypoxyprobe
• Investigators: Principal Investigator: Yana M Najjar, MD, UPMC Hillman Cancer Center

Study record dates

Study Major Dates

• Study Start (Actual): April 9, 2025
• Primary Completion (Estimated): March 31, 2027
• Study Completion (Estimated): March 31, 2027

Study Registration Dates

• First Submitted: February 13, 2025
• First Submitted That Met QC Criteria: February 13, 2025
• First Posted (Actual): February 17, 2025

Study Record Updates

• Last Update Posted (Actual): May 8, 2025
• Last Update Submitted That Met QC Criteria: May 5, 2025
• Last Verified: May 1, 2025

More Information

Terms related to this study

• Keywords: Melanoma in-transit metastases (ITMs); intra-nodal hypoxia; Tumor cell oxidative metabolism (OCR)
• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Neoplasms by Histologic Type; Skin Diseases; Signs and Symptoms, Respiratory; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Neuroendocrine Tumors; Nevi and Melanomas; Skin Neoplasms; Hypoxia; Melanoma
• Other Study ID Numbers: HCC 24-102

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No